Rhodium-catalyzed domino heterocyclization and [(3+2)+2] carbocyclization: Construction of fused tricycloheptadienes

Article abstract of DOI:10.1039/c0cc02382e

A rhodium-catalyzed domino heterocyclization and formal [(3+2)+2] carbocyclization reaction of readily available diyne-enones and alkynes was developed. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc02382e

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Rhodium-catalyzed domino heterocyclization and [(3+2)+2]
carbocyclization: construction of fused tricycloheptadienesw
Wanxiang Zhao and Junliang Zhang*
Received 6th July 2010, Accepted 24th August 2010
DOI: 10.1039/c0cc02382e
A rhodium-catalyzed domino heterocyclization and formal
[(3+2)+2] carbocyclization reaction of readily available
diyne-enones and alkynes was developed.
The design of novel methods for synthesis of polycycles contain-
ing a highly substituted carbocyclic seven-membered ring has
been intensively pursued by the synthetic community because of
its versatile applications in the synthesis of materials ranging
from biologically active molecules of pharmaceutical interest to
polymer components.1 In this context, rhodium-catalyzed carbo-
cyclization reactions are one of the most attractive methods since
they are efficient in constructing polycycles scaffolds, such as
[4+3],2,3 [3+2+2],4,5 [3+3+1],6 [5+2],1a,7 [6+1],8 [4+2+1],9
and [2+2+2+1]10 processes. Moreover, the development of
new domino reactions for constructing highly functionalized
substituted furans from easily available acyclic starting materials
has been stimulated by their appearance in many bioactive
natural products and important pharmaceuticals as well as their
being useful building blocks in organic synthesis.11 Herein, we
report the first example of rhodium(I)-catalyzed two-component
tandem heterocyclization and [(3+2)+2] carbocyclization
reaction of conjugated yne-enone,12,13 with tethered alkyne
(diyne-enones 1) and exogenous alkyne for construction of fused
5,6,7-tricycles, where 1 serves as a five-atom synthon for the
heterocyclization and the conjugated enynone section acts as
non-cyclopropane derived 3C building blocks for the [(3+2+2)]
carbocyclization.
Scheme 1 Previous work and the projected working hypothesis for
[(3+2)+2] carbocyclization.
Table 1 Screening the reaction scope via variation of diyne-enones 1
Diyne-enone 1
Time/ Yielda (%)/
h
b
Ratio of 3/30
X
R1
R2
Ph
R3
H
Entry
1
C(CO2Me)2 Ph
C(CO2Me)2 Me
1a 3
65
(3aa/3aa0: 2.2/1)
50
2
Ph
H
H
1b 7
1c 2
1d 3
(3ba/3ba0: 1.0/1)
46
3c
4
C(CO2Me)2 4-ClPh Ph
(3ca/3ca0: 1.3/1)
61
Recently, we have reported a Rh(I)-catalyzed domino nucleo-
philic addition/bicyclization of diyne-enones with alcohols via a
C(CO2Me)2 Ph
C(CO2Me)2 Ph
4-ClPh H
(3da/3da0: 2.5/1)
42
5
Ph
Ph
Ph
n-Bu 1e 10
proposed vinyl-rhodium intermediate with
a
reactive
(3ea/3ea0: 3.0/1)
45
carbocation.14 We envisaged that this vinyl–rhodium intermediate
may be trapped by alkynes undergoing a [(3+2)+2] carbocycliza-
tion to afford furan-fused tricycloheptadienes (Scheme 1).
6c
NTs
Ph
H
1f 3
(3fa/3fa0: 4 20/1)
—
7
O
Me
H
1g 3
a
b
Total yields. The ratios were determined by 1H NMR of the crude
This hypothesis was initially tested by diyne-enone 1a with
phenyl acetylene 2a under the catalysis of 5 mol% of
[RhCl(CO)2]2, and the reaction furnished fused 5,6,7-tricyclic
compound 3aa and its regioisomer 3aa0 in 57% yield with low
regioselectivity (3aa/3aa0 = 2.0/1), along with 38% yield of
[2+2+2] cycloadduct 4a.15 Further screening studies revealed
that the [2+2+2] cycloadduct could be efficiently suppressed
c
product. Some unidentified products were formed.
CO and larger amounts of phenylacetylene 2 would give
higher yield of tricyclic cycloadduct.17
With the optimal reaction conditions in hand, we next
turned to study the scope of the diyne-enone component 1
and the results are summarized in Table 1. The reaction of
substrates 1b–d, tethered with a terminal alkyne (R3 = H)
could give the corresponding cycloadducts in moderate yields
(Table 1, entries 2–4). Substrate 1e, tethered with an internal
alkyne (R3 = butyl), could also furnish the desired tricyclic
compounds in 42% total yield (Table 1, entry 5). It is
noteworthy that the reaction of 1f, with a TsN tether,
produced tricyclic 3fa in 45% yield as a single regioisomer
(420 : 1) (Table 1, entry 6), indicating the tethered atom
(o5% yield) under
Gratifyingly, we eventually found that lower pressure of
a
carbon monoxide atmosphere.16
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N, Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: (+86) 21-6223-5039
w Electronic supplementary information (ESI) available: Representative
experimental procedure and characterization of reaction products.
CCDC 744681, 744682. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0cc02382e
c
7816 Chem. Commun., 2010, 46, 7816–7818
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Table 2 Screening the reaction scope via variation of alkynes 2
the electron-density of the aryl ring, which gave 3an as a single
regioisomer (Table 2, entry 14). Gratifyingly, the sterically
bulky 2,4,6-trimethylphenylacetylene 2o can also be well
incorporated into the corresponding product to give 3ao as
the major isomer (eqn (1)).
In order to provide evidence to support the mechanism,
several control experiments were carried out (eqn (2)–(3)).
Three equivalents of MeOH were subjected to the reaction
instead of phenylacetylene and the reaction produced cyclo-
adduct 5a in 52% yield after 20 h.14 It is interesting to find that
higher yield of 5a (58%), along with 12% yield of 3aa/3aa0 was
obtained and the reaction was much faster with adding three
equivalents of phenylacetylene to this reaction (eqn (2) vs.
eqn (3)), indicating that alkyne-coordinated intermediates
IB/IB0 may exist in this domino reaction.
Alkyne 2
Time/ Yield (%)/
Ratio of 3/30
R4
R5
Entry
h
1
2
3
4
5
6
7
8
4-MeC6H4
H
H
H
H
H
2b 3.5
72 (3ab/3ab0: 3.0/1)
71 (3ac/3ac0: 10/1)
64 (3ad/3ad0: 420/1)
59 (3ae/3ae0: o1/20)
60 (3af/3af0: o1/20)
60 (3bf/3bf0: o1/20)
59 (3ag/3ag0: 1/3.2)
63 (3ah/3ah0: 1/5.0)
60 (3ai/3ai0: 10/1)
4-MeOC6H4
3,4-(MeO)2C6H3
3,5-(CF3)2C6H3
4-NO2C6H4
1b with 2f
4-MeO2CC6H4
4-AcC6H4
1-naphthyl
2c
2d 3
3
2e
2f
3
2
4
H
H
H
2g 3
2h 3
2i 3.5
9
10
11
12
1-cyclohexenyl
TsNHCH2
n-Bu/H
H
H
H
Me
2j
2k 4
2l 4.5
2m 4
3
60 (3aj/3aj0: 4.0/1)
46 (3ak/3ak0: 1/5.0)
64 (3al/3al0: 1.3/1)
36 (3am/3am0: 1.7/1)
30 (3an/3an0: 420/1)
13a Ph
14a 4-MeOC6H4
4-NO2C6H4 2n 3
ð2Þ
ð3Þ
a
Some unidentified by-products were isolated.
affects the regioselectivity. The oxygen-tethered substrate was
decomposed under the reaction conditions and could not give
the corresponding cycloadduct (Table 1, entry 7).
We next investigated the scope of the reaction by testing
various alkynes (Table 2). Interestingly, substituents on the aryl
ring of terminal arylacetylene (R5 = H) have little impact on
the yield of the carbocyclization, but have a significant impact
on the regioselectivity. For example, arylacetylenes 2c–d with
electron-donating group(s) on the aryl ring gave the corres-
ponding cycloadducts 3ac–d with high regioselectivities
(Table 2, entries 2–3); in contrast, arylacetylenes 2e–h with
electron-withdrawing group(s) led to 3ae0–h0 with high anti-
regioselectivities (Table 2, entries 4–8). The structures of 3bf0
and 3ad were further confirmed by the X-ray crystallographic
analysis.18 The reaction of 1a with 1-naphthylacetylene 2i is also
highly regioselective (10/1) to produce 3ai as the major regio-
isomer (Table 2, entry 9). The reaction of terminal substituted
alkynes 2j–l also proceeded smoothly to afford the corresponding
cycloadducts in moderate yields with moderate regioselectivities
(Table 2, entries 10–12). Gratifyingly, internal alkynes 2m–n
could also be incorporated into the products but in only 30–36%
yields, due to a competitive side reaction, intermolecular
carbocyclization of two molecules of 1a (Table 2, entries 13–14).
The result from the reaction of 1a with internal alkyne 2n
further proved that the regioselectivity heavily depends on
Scheme 2 outlines two plausible catalytic cycles (Cycles A
and B) for this [(3+2)+2] carbocyclization. The coordination
of the rhodium complex to the double alkyne moieties of 1
would give IA, which would in turn undergo oxidative cyclo-
metalation in the presence of exogenous alkyne 2 to give
tricyclic intermediates IB/IB0 with the rhodium–alkyl and
rhodium–vinyl bonds. Cycle A involves the insertion of
alkynes to form metallacycles in IB0 to generate rhodacyclo-
octadiene IC0.19 Subsequent reductive elimination would give
Scheme
2
Plausible mechanism for the rhodium-catalyzed
ð1Þ
[(3+2)+2] carbocyclization.
c
This journal is The Royal Society of Chemistry 2010
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the products 3/30 and regenerate the catalyst. Whereas Cycle B
outlines the insertion of alkyne 2 into the vinyl–Rh bond
leading to rhodacyclooctadiene IC, followed by reductive
elimination to afford the furan-fused tricycloheptadiene 3/30.
Generally, the migratory insertion of the metal–vinyl bond
(Cycle B) is more favorable.20 However, the present results can
not rule out Cycle A. The regioselectivity is much more likely
to be consistent with migratory insertion versus the stereo-
electronic effect of alkynes.
8 P. A. Wender, N. M. Deschamps and R. Sun, Angew. Chem.,
Int. Ed., 2006, 45, 3957.
9 P. A. Wender, N. M. Deschamps and G. G. Gamber,
Angew. Chem., Int. Ed., 2003, 42, 1853.
10 (a) S. Lee and I. Ojima, J. Am. Chem. Soc., 2000, 122, 2385;
(b) B. Bennacer, M. Fujiwara and I. Ojima, Org. Lett., 2004, 6,
3589; (c) B. Bennacer, M. Fujiwara, S.-Y. Lee and I. Ojima, J. Am.
Chem. Soc., 2005, 127, 17756; (d) J. Kaloko, Y. Teng and I. Ojima,
Chem. Commun., 2009, 4569; (e) For theoretical studies of the
cycloaddition mechanism see: M. M. Montero-Campillo,
J. Rodriguez-Otero and E. Cabaleiro-Lago, J. Phys. Chem. A,
2008, 112, 2423.
In conclusion, we have developed a rhodium-catalyzed
domino heterocyclization and formal [(3+2)+2] carbo-
cyclization reaction of readily available diyne-enone and
alkyne leading to fused tricyclic tricycloheptadienes. The
regioselectivity of this carbocyclization heavily depends on
both tether atom and the nature of the alkyne. Since diyne-enone
could be easily prepared by the palladium-catalyzed cross-
coupling of a-bromo(iodo)-enones with 1,6-diynes,14 this
method will be useful in organic synthesis. Further studies
including the scope, mechanism and regioselectivity are
ongoing in our laboratory and will be reported in due course.
This research was supported by 973 program
(2011CB808600), the National Natural Science Foundation
of China (20972054), Ministry of Education of PRC.
11 For recent reviews, accounts, and highlights dealing with the
synthesis of furans since 2005, see: (a) R. C. D. Brown,
Angew. Chem., Int. Ed., 2005, 44, 850; (b) S. F. Kirsch, Org.
Biomol. Chem., 2006, 4, 2076; (c) D. M. D’Souza and T. J. J.
Muller, Chem. Soc. Rev., 2007, 36, 1095; (d) N. T. Patil and
¨
Y. Yamamoto, ARKIVOC, 2007, x, 121; (e) G. Balme,
D. Bouyssi and N. Monteiro, Heterocycles, 2007, 73, 87;
(f) X. L. Hou, Z. Yang, K.-S. Yeung and H. N. C. Wong, in
Progress in Heterocyclic Chemistry, ed. G. W. Gribble and
J. A. Joule, Pergamon, Oxford, 2008, vol. 19, p. 176;
(g) S. F. Kirsch, Synthesis, 2008, 3183.
12 (a) T. Yao, X. Zhang and R. C. Larock, J. Am. Chem. Soc., 2004,
126, 11164; (b) T. Yao, X. Zhang and R. C. Larock, J. Org. Chem.,
2005, 70, 7679; (c) N. T. Patil, H. Wu and Y. Yamamoto, J. Org.
Chem., 2005, 70, 4531.
13 The work from our group, please see: (a) Y. Xiao and J. Zhang,
Angew. Chem., Int. Ed., 2008, 47, 1903; (b) Y. Xiao and J. Zhang,
Adv. Synth. Catal., 2009, 351, 617; (c) X. Yu, H. Ren, Y. Xiao and
J. Zhang, Chem.–Eur. J., 2008, 14, 8481; (d) F. Liu, Y. Yu and
J. Zhang, Angew. Chem., Int. Ed., 2009, 48, 5505; (e) Y. Xiao and
J. Zhang, Chem. Commun., 2009, 3594; (f) R. Liu and J. Zhang,
Chem.–Eur. J., 2009, 15, 9303.
14 W. Zhao and J. Zhang, Chem. Commun., 2010, 46, 4384.
15 For selective examples of [2+2+2] carbocyclization of alkynes
catalyzed by rhodium, see: (a) H. Kinoshita, H. Shinokubo and
K. Oshima, J. Am. Chem. Soc., 2003, 125, 7784; (b) T. Shibata,
T. Fujimoto, K. Yokota and K. Takagi, J. Am. Chem. Soc., 2004,
126, 8382; (c) K. Tanaka, K. Takeishi and K. Noguchi, J. Am.
Chem. Soc., 2006, 128, 4586; (d) A. Kondoh, H. Yorimitsu and
K. Oshima, J. Am. Chem. Soc., 2007, 129, 6996; (e) K. Tanaka,
A. Kamisawa, T. Suda, K. Noguchi and M. Hirano, J. Am. Chem.
Soc., 2007, 129, 12078; (f) T. Shibata, T. Uchiyama and K. Endo,
Org. Lett., 2009, 11, 3906; (g) G. Nishida, K. Noguchi, M. Hirano
and K. Tanaka, Angew. Chem., Int. Ed., 2008, 47, 3410;
(h) K. Tanaka, N. Fukawa, T. Suda and K. Noguchi, Angew.
Chem., Int. Ed., 2009, 48, 5470; (i) B. R. Galan and T. Rovis,
Angew. Chem., Int. Ed., 2009, 48, 2830; (j) S. Brun, L. Garcia,
Notes and references
1 (a) P. A. Wender, G. G. Gamber and T. J. Williams, in Modern
Rhodium-Catalyzed Organic Reactions, ed. P. A. Evans,
Wiley-VCH, Weinheim, 2005, ch 13, p. 263, and references cited
therein; (b) M. A. Battiste, P. M. Pelphrey and D. L. Wright,
Chem.–Eur. J., 2006, 12, 3438; (c) G. Rousseau and F. Homsi,
Chem. Soc. Rev., 1997, 26, 453.
2 (a) H. M. L. Davies, H. D. Smith and O. Korkor, Tetrahedron
Lett., 1987, 28, 1853; (b) H. M. L. Davies and L. M. Hodges,
J. Org. Chem., 2002, 67, 5683; (c) R. P. Reddy and H. M. L.
Davies, J. Am. Chem. Soc., 2007, 129, 10312; (d) J. P. Olson and
H. M. L. Davies, Org. Lett., 2008, 10, 573; (e) B. D. Schwartz,
J. R. Denton, Y. Lian and H. M. L. Davies, J. Am. Chem. Soc.,
2009, 131, 8329; (f) H. M. L. Davies, R. L. Calvo, R. J. Townsend,
P. Ren and R. M. Churchill, J. Org. Chem., 2000, 65, 4261.
3 For examples of palladium-catalyzed [4+3] cyclizations, see:
(a) B. M. Trost and D. T. MacPherson, J. Am. Chem. Soc.,
1987, 109, 3483; (b) M. Gulı
and J. L. Mascarenas, J. Am. Chem. Soc., 2007, 129, 11026;
(c) B. Trillo, F. Lopez, M. Gulıas, L. Castedo and
J. L. Mascarenas, Angew. Chem., Int. Ed., 2008, 47, 951.
4 (a) J. Barluenga, R. Viecente, P. Barrio, L. A. Lopez, M. Toma
as, J. Duran, F. Lopez, L. Castedo
´ ´ ´
I. Gonzalez, A. Torrent, A. Dachs, A. Pla-Quintana, T. Parellab
´
and A. Roglans, Chem. Commun., 2008, 4339.
´
´
16 For carbon monoxide effects in Rh-catalyzed cyclization, see:
(a) T. Makino and K. Itoh, J. Org. Chem., 2004, 69, 395;
(b) M. Montag, I. Efremenko, R. Cohen, L. J. W. Shimon,
G. Leitus, Y. Diskin-Posner, Y. Ben-David, H. Salem, J. M. L.
Martin and D. Milstein, Chem.–Eur. J., 2010, 16, 328.
´
´
s
and J. Borge, J. Am. Chem. Soc., 2004, 126, 14354; (b) P. A. Evans
and P. A. Inglesby, J. Am. Chem. Soc., 2008, 130, 12838.
5 For examples of nickel-catalyzed [3+2+2] cyclizations, see:
(a) S. Saito, M. Matsuda and S. Kamagawa, J. Am. Chem. Soc.,
2004, 126, 10540; (b) S. Komagawa and S. Saito, Angew. Chem.,
Int. Ed., 2006, 45, 2446; (c) S. Saito, S. Komagawa, I. Azumaya
and M. Masuda, J. Org. Chem., 2007, 72, 9115; (d) S. Komagawa,
K. Takeuchi, I. Sotome, I. Azumaya, H. Masu, R. Yamasakai and
S. Saito, J. Org. Chem., 2009, 74, 3323.
17 Please see the details in supporting information.
18 CCDC 744681 (3bf0), and 744682 (3ad) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge form The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/datarequest/cif.
19 For regioselective insertion of polarized alkynes to form
metallacycles in which the electron-withdrawing group is adjacent
to the metal, see: (a) M. Paneque, C. M. Posadas, M. L. Poveda,
6 S. Y. Kim, S. I. Lee, S. Y. Choi and Y. K. Chung, Angew. Chem.,
Int. Ed., 2008, 47, 4914.
´
7 (a) H. A. Wegner, A. de Meijere and P. A. Wender, J. Am. Chem.
Soc., 2005, 127, 6530; (b) P. A. Wender, L. O. Haustedt, J. Lim,
J. A. Love, T. J. Williams and J.-Y. Yoon, J. Am. Chem. Soc.,
2006, 128, 6302; (c) S. I. Lee, S. Y. Park, J. H. Park, I. G. Jung,
S. Y. G. Choi and Y. K. Chung, J. Org. Chem., 2006, 71, 91;
(d) P. A. Wender, L. E. Sirois, R. T. Stemmler and T. J. Williams,
Org. Lett., 2010, 12, 1604; (e) P. A. Wender, R. T. Stemmler and
L. E. Sirois, J. Am. Chem. Soc., 2010, 132, 2532; (f) F. Inagaki,
K. Sugikubo, Y. Miyashita and C. Mukai, Angew. Chem., Int. Ed.,
2010, 49, 2206.
N. Rendo
´
n, E. Alvarez and K. Mereiter, Chem.–Eur. J., 2007, 13,
5160; (b) R. K. Friedman and T. Rovis, J. Am. Chem. Soc., 2009,
131, 10775.
20 For selected examples of metal–vinyl versus metal–alkyl migratory
insertion, see: (a) Y. Wakatsuki, K. Aoki and H. Yamazaki, J. Am.
Chem. Soc., 1979, 101, 1123; (b) K. M. Doxsee and J. K. M.
Mouser, Organometallics, 1990, 9, 3012; (c) T. Shibata,
Y.-k. Tahara, K. Tamura and K. Endo, J. Am. Chem. Soc.,
2008, 130, 3451; (d) P. A. Evans, J. R. Sawyer and
P. A. Inglesby, Angew. Chem., Int. Ed., 2010, 49, 5746.
c
7818 Chem. Commun., 2010, 46, 7816–7818
This journal is The Royal Society of Chemistry 2010